Abstract Individuals who are exposed to life-threatening trauma are at significant risk of developing post-traumatic stress disorder (PTSD). People with PTSD experience extreme psychological distress by repeatedly reliving their trauma through intrusive flashback memories. These memories are accompanied by other symptoms, including emotional numbing, avoidance of stimuli associated with the trauma, and a persistent state of hypervigilance. In addition to the psychological manifestations, PTSD is also associated with enhanced progression of coronary atherosclerosis and an increased likelihood of experiencing a myocardial infarction. However, the impact of PTSD on the ischemic heart has not been well studied. Specifically, it is unclear whether PTSD induces myocardial changes that influence the extent of ischemia-induced injury. Such studies are difficult to conduct in human patients because PTSD is associated with increased rates of smoking, sedentary lifestyle, diabetes, depression, and other factors that influence cardiovascular function. Thus, our laboratory is using an animal model of PTSD to examine its impact on the myocardial response to ischemic injury. The model is advantageous because it permits the controlled induction of myocardial ischemia independent of atherosclerotic blockage of coronary arteries, and it avoids the confounding cardiovascular risk factors mentioned above. Our preliminary studies provide evidence that this animal model of PTSD induces changes in the heart that increase myocardial sensitivity to ischemic injury. Some of the physiological and behavioral alterations induced by this model can be reversed or prevented by drugs that are used to treat human PTSD patients. However, it is unknown whether these agents can reverse the increased myocardial sensitivity to ischemic injury that results from this exposure to this model. Therefore, Aim 1 of this study is to determine whether the psychosocial stress-induced increase in myocardial sensitivity to ischemic injury can be reversed or prevented by pharmacotherapy. Exposure to this rat model of PTSD increases cerebral and hippocampal production of pro-inflammatory cytokines, increases signaling through the pro-inflammatory NF- ?B signaling pathway, and increases the production of reactive oxygen species. Inflammation and oxidative stress are important components of myocardial ischemic injury. However, it is unknown whether the pro- inflammatory events that have been reported in the brain following exposure to this PTSD model also occur in the heart. Aim 2 of this study is to identify the mechanism by which this PTSD model increases myocardial sensitivity to ischemic injury. Finally, women are at significantly greater risk of developing PTSD than men. However, few animal models of PTSD have included females because of complexities associated with the effects of the estrous cycle on the stress response. Aim 3 of this study is to examine the influence of estrous stage on behavioral responses and myocardial sensitivity to ischemic injury in female rats exposed to our animal model of PTSD.